Enhanced or unregulated production of tumor necrosis factor α (TNF-α) has been implicated in inflammatory, allergic, and autoimmune diseases. It has been shown that Adenosine 3′,5′-cyclic monophosphate (cAMP) plays a role in TNF-α production. Elevation of cAMP in inflammatory leukocytes inhibits their activation and the subsequent release of inflammatory mediators, including TNF-α. The primary cellular mechanism for the inactivation of cAMP is the breakdown of cAMP by a family of isoenzymes referred to as cyclic nucleotide phosphodiesterases (PDE). The inhibition of PDE, in particular type IV PDE (PDE4), is effective in the inhibition of TNF-α release.
For example, 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione is a PDE4 inhibitor that is currently under investigation as an anti-inflammatory for the treatment of a variety of conditions, including asthma, chronic obstructive pulmonary disease, psoriasis and other allergic, autoimmune and rheumatologic conditions. S-enantiomer form of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione can be prepared by reacting (S)-aminosulfone 1 with intermediate 2.

Currently, (S)-aminosulfone 1 is prepared by converting 3-ethoxy-4-methoxybenzaldehyde 3 to racemic aminosulfone 5 followed by resolution with N—Ac-L-Leu.

The current procedure for preparing racemic aminosulfone 5, as shown in the above scheme, is inefficient due to its long process cycle time and low yield. Alternative methods for the preparation of racemic aminosulfone 5, particularly for manufacturing scale production, are thus desirable.